Molecular and Structural Evolution of Cytochrome P450 Aromatase.

Giovanna Di Nardo,Chao Zhang,Gianfranco Gilardi,Anna Giulia Marcelli

doi:10.3390/ijms22020631

Giovanna Di Nardo, Chao Zhang + Show 2 more

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https://doi.org/10.3390/ijms22020631

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Abstract

Aromatase is the cytochrome P450 enzyme converting androgens into estrogen in the last phase of steroidogenesis. As estrogens are crucial in reproductive biology, aromatase is found in vertebrates and the invertebrates of the genus Branchiostoma, where it carries out the aromatization reaction of the A-ring of androgens that produces estrogens. Here, we investigate the molecular evolution of this unique and highly substrate-selective enzyme by means of structural, sequence alignment, and homology modeling, shedding light on its key role in species conservation. The alignments led to the identification of a core structure that, together with key and unique amino acids located in the active site and the substrate recognition sites, has been well conserved during evolution. Structural analysis shows what their roles are and the reason why they have been preserved. Moreover, the residues involved in the interaction with the redox partner and some phosphorylation sites appeared late during evolution. These data reveal how highly substrate-selective cytochrome P450 has evolved, indicating that the driving forces for evolution have been the optimization of the interaction with the redox partner and the introduction of phosphorylation sites that give the possibility of modulating its activity in a rapid way.

Highlights

Aromatase is the enzyme that converts androgens into estrogens through a three-step reaction that allows the aromatization of the A-ring of the steroid molecule [1,2]
The enzyme belongs to the cytochrome P450 (P450s) superfamily that comprises thousands of enzymes involved in the metabolism of endogenous and exogenous substrates [3,4,5]
For all the analyses performed in this work, the residue numbers refer to the sequence of human aromatase (CYP19A1, Uniprot ID P11511)

Summary

Introduction

Aromatase is the enzyme that converts androgens into estrogens through a three-step reaction that allows the aromatization of the A-ring of the steroid molecule [1,2]. The enzyme belongs to the cytochrome P450 (P450s) superfamily that comprises thousands of enzymes involved in the metabolism of endogenous and exogenous substrates [3,4,5]. The origin of such a large number of enzymes is still controversial, even though the presence of a common ancient precursor, CYP51 (lanosterol 14alpha-demethylase), for both prokaryotes and eukaryotes has been hypothesized [6]. The P450 superfamily is composed of two groups of enzymes Depending on their substrate recognition abilities, one group comprises P450s that catalyze specific reactions on specific endogenous substrates; a second group includes enzymes that have evolved towards broad substrate selectivity, usually employed for xenobiotic metabolism, as in the case of mammalian liver proteins. While for the second group, it can be hypothesized that evolution has widened their substrate selectivity, for the first one, it is not clear how molecular evolution has worked

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